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US6436929B1 - Cyclothiocarbamate derivatives as progesterone receptor modulators - Google Patents

Cyclothiocarbamate derivatives as progesterone receptor modulators Download PDF

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Publication number
US6436929B1
US6436929B1 US09/552,354 US55235400A US6436929B1 US 6436929 B1 US6436929 B1 US 6436929B1 US 55235400 A US55235400 A US 55235400A US 6436929 B1 US6436929 B1 US 6436929B1
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Prior art keywords
substituted
alkyl
group
alkoxy
aryl
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Inventor
Puwen Zhang
Andrew Fensome
Eugene A. Terefenko
Lin Zhi
Todd K. Jones
James P. Edwards
Christopher M. Tegley
Jay E. Wrobel
Mark A. Collins
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Wyeth LLC
Ligand Pharmaceuticals Inc
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Wyeth LLC
Ligand Pharmaceuticals Inc
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Priority to UA2001117768A priority Critical patent/UA73119C2/uk
Priority to US09/552,354 priority patent/US6436929B1/en
Application filed by Wyeth LLC, Ligand Pharmaceuticals Inc filed Critical Wyeth LLC
Priority to JP2000615600A priority patent/JP4958338B2/ja
Priority to CN008070997A priority patent/CN1131856C/zh
Priority to IL14629800A priority patent/IL146298A0/xx
Priority to CZ20013952A priority patent/CZ20013952A3/cs
Priority to EP00930266A priority patent/EP1175411B1/fr
Priority to EA200101181A priority patent/EA004511B1/ru
Priority to NZ515353A priority patent/NZ515353A/xx
Priority to HU0203332A priority patent/HUP0203332A3/hu
Priority to SG200400081A priority patent/SG120970A1/en
Priority to PCT/US2000/011749 priority patent/WO2000066570A1/fr
Priority to ES00930266T priority patent/ES2301482T3/es
Priority to HK02104862.5A priority patent/HK1043789A1/zh
Priority to AU48119/00A priority patent/AU766801B2/en
Priority to KR1020017014085A priority patent/KR100732692B1/ko
Priority to PL00351083A priority patent/PL351083A1/xx
Priority to CA002371712A priority patent/CA2371712C/fr
Priority to AT00930266T priority patent/ATE386729T1/de
Priority to SK1592-2001A priority patent/SK15922001A3/sk
Priority to BR0010214-8A priority patent/BR0010214A/pt
Priority to MXPA01011287A priority patent/MXPA01011287A/es
Priority to GEAP20006120A priority patent/GEP20043181B/en
Priority to DK00930266T priority patent/DK1175411T3/da
Priority to TR2001/03285T priority patent/TR200103285T2/xx
Priority to DE60038108T priority patent/DE60038108T2/de
Assigned to LIGAND PHARMACEUTICALS, INC. reassignment LIGAND PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: EDWARDS, JAMES P., JONES, TODD K., ZHI, LIN, TEGLEY, CHRISTOPHER M.
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Priority to NO20015381A priority patent/NO321370B1/no
Priority to BG106080A priority patent/BG65277B1/bg
Priority to US10/140,034 priority patent/US7081457B2/en
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Priority to US12/420,085 priority patent/US8329690B2/en
Assigned to WYETH LLC reassignment WYETH LLC CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: WYETH
Priority to JP2011249051A priority patent/JP5523430B2/ja
Priority to US13/679,055 priority patent/US8466146B2/en
Priority to US13/905,515 priority patent/US8796266B2/en
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Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to compounds which are agonists of the progesterone receptor, their preparation and utility. This invention also provides methods of using these compounds in the inducement of contraception and the treatment and/or prevention of dysfunctional bleeding, uterine leiomyomata, endometriosis, polycystic ovary syndrome, and carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, and prostate.
  • Intracellular receptors form a class of structurally related gene regulators known as “ligand dependent transcription factors” (R. M. Evans, Science, 240, 889, 1988).
  • the steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).
  • PR progesterone receptor
  • ER estrogen receptor
  • AR glucocorticoid receptor
  • MR mineralocorticoid receptor
  • the natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as ligands.
  • a ligand Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell's DNA. Once bound to the DNA the complex modulates the production of mRNA and protein encoded by that gene.
  • a compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist.
  • PR agonists are known to play an important role in the health of women.
  • PR agonists are used in birth control formulations, typically in the presence of an ER agonist, alternatively they may be used in conjunction with a PR antagonist.
  • ER agonists are used to treat the symptoms of menopause, but have been associated with a proliferative effect on the uterus which can lead to an increased risk of uterine cancers.
  • Co-administration of a PR agonist reduces/ablates that risk.
  • the compounds of this invention have been shown to act as competitive inhibitors of progesterone binding to the PR and act as agonists in functional models, either/or in-vitro and in-vivo. These compounds may be used for contraception, in the treatment of fibroids, endometriosis, breast, uterine, ovarian and prostate cancer, and post menopausal hormone replacement therapy.
  • Sakata et al. JP 07159917, CA 123:301431 teach that certain benzoxazin-2-thione compounds such as compound A can be used as photographic materials.
  • Kim et al. disclose that some imidazole substituted benzothiazines, such as compound B, can be used as cardiotonics (U.S. Pat. No. 5,171,851 and EP 510235). More recently, Young et al. (WO95/20389) and Christ et al. (WO98/14436) claimed benzoxazin-2-thiones such as compound C as inhibitors of HIV reverse transcriptase.
  • This invention provides compounds of the formula:
  • R 1 and R 2 are independent substituents selected from the group of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A , or NR B COR A ;
  • R 1 and R 2 are fused to form a spirocyclic ring selected from a), b) or c), below, each spirocyclic ring being optionally substituted by from 1 to 3 substituents selected from H or C 1 -C 3 alkyl:
  • R A is selected from H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, amino, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl;
  • R B is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl
  • R 3 is H, OH, NH 2 , C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 6 alkenyl, substituted C 1 to C 6 alkenyl, alkynyl, or substituted alkynyl, or COR C ;
  • R C is selected from H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl;
  • R 4 is selected from H, halogen, CN, NO 2 , C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, or substituted C 1 to C 6 aminoalkyl;
  • R 5 is selected from groups a), b), or c) below:
  • R 5 is a trisubstituted benzene ring containing the substituents X, Y and Z as shown below:
  • X is selected from the group including halogen, CN, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 thioalkoxy, substituted C 1 to C 3 thioalkoxy, C 1 to C 3 aminoalkyl, substituted C 1 to C 3 aminoalkyl, NO 2 , C 1 to C 3 perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, COR D , OCOR D , or NR E COR D ;
  • R D is H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl;
  • R E is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl
  • Y and Z are independent substituents selected from the group of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 3 alkyl, or C 1 to C 3 thioalkoxy; or
  • R 5 is a five or six membered heterocyclic ring with 1, 2, or 3 ring heteroatoms selected from the group of O, S, S(O), S(O 2 ) or NR 6 and containing one or two independent substituents from the group of H, halogen, CN, NO 2 and C 1 to C 3 alkyl, C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, COR F , or NR G COR F ;
  • R F is H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl;
  • R G is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl
  • R 6 is H, or C 1 to C 3 alkyl
  • R 5 is a six membered ring with the structure:
  • X 1 is N or CX 2 ,
  • X 2 is halogen, CN, or NO 2 ,
  • Q 1 is S, NR 7 , or CR 8 R 9 ;
  • R 7 is selected from the group of CN, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, or substituted heterocyclic, SO 2 CF 3 , OR 11 or NR 11 R 12 ;
  • R 8 and R 9 are independent substituents selected from the group of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO 2 , CN, or CO 2 R 10 ;
  • R 10 is C 1 to C 3 alkyl; or CR 8 R 9 comprise a six membered ring as shown by the structure below:
  • Q 2 is selected from the moieties:
  • R 11 , R 12 and R 13 are independently selected from H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl or sulfonyl;
  • R 11 , R 12 and R 13 in groups of the compounds described herein are H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, —C(O)—(C 1 to C 6 alkyl), —S(O) 2 —(C 1 to C 6 alkyl), phenyl or benzyl.
  • R 1 is H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A , or NR B COR A ;
  • R 2 is H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A , or NR B COR A ;
  • R 1 and R 2 are fused to form:
  • R A is H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl;
  • R B is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl
  • R 3 is H, OH, NH 2 , C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 6 alkenyl, substituted C 1 to C 6 alkenyl, alkynyl, or substituted alkynyl, or COR C ;
  • R C is H, C 1 to C 4 alkyl, substituted C 1 to C 4 alkyl, aryl, substituted aryl, C 1 to C 4 alkoxy, substituted C 1 to C 4 alkoxy, C 1 to C 4 aminoalkyl, or substituted C 1 to C 4 aminoalkyl;
  • R 4 is H, halogen, CN, NO 2 , C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, or substituted C 1 to C 6 aminoalkyl;
  • R 5 is a trisubstituted benzene ring containing the substituents X, Y and Z as shown below,
  • X is taken from the group including halogen, CN, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 thioalkoxy, substituted C 1 to C 3 thioalkoxy, C 1 to C 3 aminoalkyl, substituted C 1 to C 3 aminoalkyl, NO 2 , C 1 to C 3 perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3 heteroatoms, COR D , OCOR D , or NR E COR D ;
  • R D is H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl;
  • R E is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl
  • Y and Z are independent substituents taken from the group of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 3 alkyl, or C 1 to C 3 thioalkoxy; or
  • R 5 is a five or six membered ring with 1, 2, or 3 heteroatoms from the group including O, S, SO, SO 2 or NR 6 and containing one or two independent substituents from the group including H, halogen, CN, NO 2 and C to C 3 alkyl, C 1 to C 3 alkoxy,
  • R 6 is H, or C 1 to C 3 alkyl
  • Q 1 is S, NR 7 , CR 8 R 9 ;
  • R 7 is selected from CN, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, SO 2 CF 3 , OR 11 or NR 11 R 12 ;
  • R 8 and R 9 are independent substituents from the group including H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO 2 , CN or CO 2 R 10 ;
  • R 10 is C 1 to C 3 alkyl; or CR 8 R 9 comprise a six membered ring as shown by the structure below
  • Q 2 is selected from the moieties:
  • R 11 , R 12 and R 13 are independently selected from H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl or sulfonyl;
  • R 1 and R 2 are independently selected from the group of C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, or spirocyclic alkyl constructed by fusing R 1 and R 2 to form a 3 to 6 membered spirocyclic ring;
  • R 3 is H, OH, NH 2 , C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, or COR C ;
  • R C is H, C 1 to C 4 alkyl, or C 1 to C 4 alkoxy
  • R 4 is H, halogen, NO 2 , C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
  • R 5 is a disubstituted benzene ring containing the substituents X, and Y as shown below:
  • X is selected from the group of halogen, CN, C 1 to C 3 alkoxy, C 1 to C 3 alkyl, NO 2 , C 1 to C 3 perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3 heteroatoms, or C 1 to C 3 thioalkoxy;
  • Y is a substituent selected from the group of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 4 alkyl, or C 1 to C 3 thioalkoxy; or
  • R 5 is a five membered ring with the structure shown below:
  • U is O, S, or NR 6 ;
  • R 6 is H, or C 1 to C 3 alkyl, or C 1 to C 4 CO 2 alkyl;
  • X′ is selected from the group including halogen, CN, NO 2 , C 1 to C 3 alkyl or C 1 to C 3 alkoxy;
  • Y′ is selected from the group of H and C 1 to C 4 alkyl
  • R 5 is a six membered ring with the structure:
  • X 1 is N or CX 2 ,
  • X 2 is halogen, CN, or NO 2 ,
  • Q is S, NR 7 , or CR 8 R 9 ;
  • R 7 is selected from the group of CN, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, or SO 2 CF 3 ;
  • R 8 and R 9 are independent substituents selected from the group of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO 2 , CN or CO 2 R 10 ;
  • R 10 is C 1 to C 3 alkyl
  • CR 8 R 9 a six membered ring as shown by the structure below
  • R 1 and R 2 are independently selected from the group of CH 3 and spirocyclic alkyl constructed by fusing R 1 and R 2 to form a 6 membered spirocyclic ring;
  • R 3 is H, OH, NH 2 , CH 3 , substituted methyl, or COR C ;
  • R C is H, C 1 to C 3 alkyl, or C 1 to C 4 alkoxy
  • R 4 is H, halogen, or C 1 to C 3 alkyl
  • R 5 is a disubstituted benzene ring containing the substituents X and Y as shown below
  • X is selected from the group of halogen, CN, methoxy, NO 2 , or 2-thiazole;
  • Y is a substituent selected from H and F;
  • R 5 is a five membered ring with the structure:
  • U is O, S, or NH
  • X is selected from the group of halogen, CN, NO 2 ;
  • Y is from the group of H and C 1 to C 4 alkyl
  • Q 1 is selected from S, NR 7 , or CR 8 R 9 ;
  • R 7 is selected from the group of CN, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, or SO 2 CF 3 ;
  • R 8 and R 9 are independent substituents selected from the group of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO 2 , CN or CO 2 R 10 ;
  • R 10 is C 1 to C 3 alkyl; or CR 8 R 9 comprise a six membered ring of the structure below:
  • Another preferred subgroup of this invention comprises compounds of the formula:
  • R 1 and R 2 are independently selected from the group of CH 3 and spirocyclic alkyl constructed by fusing R 1 and R 2 to form a 6 membered spirocyclic ring;
  • R 3 is H, OH, NH 2 , CH 3 , substituted methyl, or COR C ;
  • R C is H, C 1 to C 3 alkyl, or C 1 to C 4 alkoxy
  • R 4 is H, halogen, or C 1 to C 3 alkyl
  • R 5 is a disubstituted benzene ring containing the substituents X and Y as shown below
  • X is selected from the group of halogen, CN, methoxy, NO 2 , or 2-thiazole;
  • Y is a substituent selected from H and F;
  • R 5 is a five membered ring with the structure:
  • U is O, S, or NH
  • X is selected from the group of halogen, CN, NO 2 ;
  • Y is from the group of H and C 1 to C 4 alkyl
  • Q 2 is selected from the moieties:
  • R 11 , R 12 and R 13 are independently selected from H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl or sulfonyl;
  • the compounds of this invention have been shown to act as competitive inhibitors of progesterone binding to the PR and act as agonists in functional models, either/or in-vitro and in-vivo. These compounds may be used for contraception, in the treatment of fibroids, endometriosis, breast, uterine, ovarian and prostate cancer, and post menopausal hormone replacement therapy.
  • the compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to the stereochemistry in Formula I, the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
  • alkyl is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having one to eight carbon atoms, preferably one to six carbon atoms; “alkenyl” is intended to include both straight- and branched-chain alkyl groups with at least one carbon-carbon double bond and two to eight carbon atoms, preferably one to six carbon atoms; “alkynyl” group is intended to cover both straight- and branched-chain alkyl groups with at least one carbon-carbon triple bond and two to eight carbon atoms, preferably two to six carbon atoms.
  • substituted alkyl refers to alkyl, alkenyl, and alkynyl as just described having one or more substituents from the group including halogen, CN, OH, NO 2 , amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio.
  • substituents may be attached to any carbon of an alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety.
  • aryl is used herein to refer to an aromatic system which may be a single ring or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system.
  • the aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, and phenanthryl.
  • substituted aryl refers to aryl as just defined having one to four substituents from the group including halogen, CN, OH, NO 2 , amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
  • heterocyclic is used herein to describe a stable 4- to 7-membered monocyclic or a stable multicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group including N, O, and S atoms.
  • the N and S atoms may be oxidized.
  • the heterocyclic ring also includes any multicyclic ring in which any of above defined heterocyclic rings is fused to an aryl ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable.
  • heterocyclic groups include, for example, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and isoquinolinyl.
  • substituted heterocyclic is used herein to describe the heterocyclic group just defined having one or more substituents selected from the group which includes halogen, CN, OH, NO 2 , amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
  • alkoxy is used herein to refer to the OR group, where R is alkyl or substituted alkyl.
  • aryloxy is used herein to refer to the OR group, where R is aryl or substituted aryl.
  • alkylcarbonyl is used herein to refer to the RCO group, where R is alkyl or substituted alkyl.
  • alkylcarboxy is used herein to refer to the COOR group, where R is alkyl or substituted alkyl.
  • aminoalkyl refers to both secondary and tertiary amines wherein the alkyl or substituted alkyl groups, containing one to eight carbon atoms, which may be either same or different and the point of attachment is on the nitrogen atom.
  • halogen refers to Cl, Br, F, and I elements.
  • the compounds of this invention are generally prepared by employing the suitable coupling reaction as a final step.
  • a suitable organo metallic reagent e.g. Grignard reagent
  • Ring closure of carbinol 2 to yield benzoxazin-2-ones 3 is commonly effected by a condensing agent such as carbonyldiimidazole, phosgene, dimethylcarbonate, or diethylcarbonate in a suitable nonprotic solvent such as THF at temperatures ranging from room temperature to 65° C.
  • a condensing agent such as carbonyldiimidazole, phosgene, dimethylcarbonate, or diethylcarbonate in a suitable nonprotic solvent such as THF at temperatures ranging from room temperature to 65° C.
  • the arylation of benzoxazin-2-ones 3 to yield 4 can be effected by various coupling reactions including Suzuki, Stille reactions. These reactions are commonly performed in the presence of transition metallic catalyst, e.g., palladium or nickel complex often with phosphino ligands, e.g., Ph 3 P, dppf, dppe or palladium acetate.
  • an appropriately substituted nucleophilic reagent e.g., aryl boronic acid, arylstannane, or aryl zinc compound
  • benzoxazinones 3 is coupled with benzoxazinones 3 to give 4.
  • the commonly used bases include, but are not limited to, sodium bicarbonate, sodium carbonate, potassium phosphate, barium carbonate, or potassium acetate.
  • the most commonly used solvents in these reactions include benzene, DMF, isopropanol, ethanol, DME, ether, acetone, or a mixture of above solvents and water.
  • the coupling reaction is generally executed under an inert atmosphere such as nitrogen or argon at temperatures ranging from room temperature to 95° C.
  • Benzoxazinones 3 can be converted into a nucleophile such as boronic acid which can be coupled with an appropriate electrophile, e.g., aryl bromide or aryl iodide, to yield 4 employing the coupling reaction condition as described above.
  • the transformation of 3 into 5 can be effected by treating 3 with an organo metallic reagent, e.g., n-BuLi, in a nonprotic solvent such as THF or ether followed by quenching the reaction solution with a suitable electrophile, such as trimethyl borate, triisopropyl borate, or zinc chloride at temperatures ranging from ⁇ 78° C. to room temperature under an inert atmosphere such as argon or nitrogen.
  • organo metallic reagent e.g., n-BuLi
  • a suitable electrophile such as trimethyl borate, triisopropyl borate, or zinc chloride at temperatures ranging from ⁇ 78° C. to room temperature under an iner
  • Scheme Ia illustrates an alternative approach leading to the benzoxazinones 3.
  • an appropriate aniline 1 is protected with a suitable alkoxy carbonyl protective group including but not limited to allenoxy carbonyl, t-butoxy carbonyl, benzoxy carbonyl, ethoxy carbonyl, or methoxy carbonyl in a suitable solvent such as THF, acetonitrile, with or without presence of a base either as a catalyst or as an acid scavenger.
  • the protected aniline is then treated with a suitable organo metallic reagent such as organo lithium agent or Grignard reagent in the same fashion as to prepare compound 2 to give the carbinol 6.
  • Scheme II describes the procedures to prepare benzoxazinones bearing two different substituents at position-4.
  • the Weinreb amide 8 can be prepared from an appropriately substituted isatoic anhydride 7 when treated with N-, O-dimethylhydroxyl-amine hydrochloride salt in a protic solvent such as ethanol, isopropanol at reflux under an inert atmosphere such as argon or nitrogen.
  • Coupling of amide 8 with an aryl electrophile such as aryl boronic acid or arylstannane to give 9 can be effected by employing a typical coupling reaction such as Suzuki, Stille coupling procedure in a similar fashion as described for the preparation of benzoxazinones 4.
  • organo metallic compounds e.g., alkyllithium, alkynyllithium, aryllithium, or their Grignard counterpart in a nonprotic solvent such as THF or ether under an inert atmosphere such as argon or nitrogen at ⁇ 78° C. to room temperature affords amino ketone 10.
  • Conversion of ketone 10 to carbinol 11 can be effected by treatment of 10 with an organo metallic reagent such as alkyl alkynyl, or aryl Grignard compound in a nonprotic solvent such as THF or ether under an inert atmosphere such as argon or nitrogen at ⁇ 78° C. to room temperature.
  • Conversion of ketone 10 to carbinol 11 can also be effected by reduction of ketone group of 10 to the carbinol moiety of 11 using an appropriate reducing reagent such as lithium aluminum hydride, sodium borohydride in a suitable solvent such as THF, ether, or anhydrous alcohol under an inert atmosphere in the temperature range from 0° C. to the boiling point of the solvent.
  • Ring closure of carbinol 11 to produce the compounds of this invention can be accomplished with condensing agents such as carbonyldiimidazole, phosgene, dimethylcarbonate, or diethylcarbonate in a suitable nonprotic solvent such as THF at temperatures ranging from room temperature to 65° C.
  • ortho-amino ketone 10 can be prepared by treatment of ortho-amino benzonitrile 14 with an organo metallic compound such as organo lithium reagent or Gringard reagent in a suitable solvent such as THF or ether under an inert atmosphere such as argon or nitrogen at temperatures ranging from ⁇ 78° C. to room temperature as illustrated in Scheme III.
  • organo metallic compound such as organo lithium reagent or Gringard reagent
  • a suitable solvent such as THF or ether
  • an inert atmosphere such as argon or nitrogen
  • Benzonitrile 14 can be readily prepared from an appropriately substituted benzonitrile such as bromobenzonitrile 13 using a suitable coupling reaction such as Stille or Suzuki protocol carried out in a similar fashion as described for the preparation of the Weinreb amide 9.
  • Scheme IV depicts an approach to prepare benzoxazinones with a low perfluoroalkyl substituent at position-4, e.g. R 6 is trifluoromethyl group.
  • An appropriately substituted chloroaniline 15 was protected with a suitable protective group such as pivaloyl chloride or di-tert-butyl pyrocarbonate to give protected aniline 16 in a suitable solvent such as acetonitrile, acetone, THF, methylene chloride, or a mixture of solvent such as methylene chloride and water under an inert atmosphere such as argon or nitrogen at temperatures ranging from 0° C. to 70° C.
  • a suitable solvent such as acetonitrile, acetone, THF, methylene chloride, or a mixture of solvent such as methylene chloride and water under an inert atmosphere such as argon or nitrogen at temperatures ranging from 0° C. to 70° C.
  • a suitable base such as sodium carbonate, sodium bicarbonate, or potassium carbonate may be needed when the reaction produces an acid as a side-product such as hydrochloride.
  • an appropriate alkyllithium such as n-butyllithium or s-butyllithium followed by reaction with a low perfluorocarboxy derivatives, e.g., trifluoroacetyl chloride, 1-(trifluoroacetyl)-imidazole, or ethyl trifluoroacetate in a nonprotic solvent such as ether or THF under an inert atmosphere such as argon or nitrogen at ⁇ 78° C. to ambient temperature gives the protective ortho-amino ketones.
  • an appropriate alkyllithium such as n-butyllithium or s-butyllithium
  • a low perfluorocarboxy derivatives e.g., trifluoroacetyl chloride, 1-(trifluoroacetyl)-imidazole
  • Subsequent removal of the protecting group can be effected by reaction of protected amino ketones with a suitable acid such as TFA, 3N aqueous hydrochloride solution in a suitable solvent such as methylene chloride or water at 0° C. to boiling point of the solvent to afford ortho-amino ketone 17.
  • a suitable acid such as TFA, 3N aqueous hydrochloride solution in a suitable solvent such as methylene chloride or water at 0° C. to boiling point of the solvent to afford ortho-amino ketone 17.
  • 6-chlorobenzoxazinones 19 from 17 can be accomplished in the same fashion as described for the synthesis of benzoxazinone 12 from ketone 10.
  • Coupling of 19 with an aryl group to yield 12 can be effected by a nickel complex catalyzed coupling reaction.
  • the palladium catalysts proved not to be an efficient catalyst in this coupling process.
  • the coupling reaction of 19 with an appropriate aryl boronic acid can be accomplished in the presence of a suitable base such as potassium phosphate and a catalyst of nickel (0 or II) complex, e.g.
  • a nickel complex of 1,2-bis(diphenylphosphino)ethane, 1,1′-bis(diphenylphosphino)ferrocene, or triphenylphosphine a nickel complex of 1,2-bis(diphenylphosphino)ethane, 1,1′-bis(diphenylphosphino)ferrocene, or triphenylphosphine.
  • solvents in the reaction include dioxane or THF.
  • the coupling reaction is generally executed under an inert atmosphere such as nitrogen or argon at temperatures ranging from ambient temperature to 95° C.
  • benzoxazin-2-ones 3 or 12 into benzoxazin-2-thiones 20 or 21 can be accomplished by treatment of 3 or 12 with a suitable sulfur reagent such as Lawesson's reagent in a nonprotic solvent such as o-xylene, chlorobenzene, or toluene under an inert atmosphere such as argon or nitrogen at reflux.
  • a suitable sulfur reagent such as Lawesson's reagent in a nonprotic solvent such as o-xylene, chlorobenzene, or toluene under an inert atmosphere such as argon or nitrogen at reflux.
  • Schemes VI and VII describe the synthesis of other benzoxazinone bioisosteres.
  • compound 22 can be formed by treatment of amino carbinol 11 with an appropriate ketene-S,S-acetals (at least one of R 16 or R 17 is an electron withdrawing group) in a suitable solvent such as toluene or anhydrous ethanol under an inert atmosphere such as nitrogen or argon at reflux.
  • compound 23 can be formed by reaction of amino carbinol 11 with an appropriate imino-S,S-acetals or imino-acetals (R 18 is an electron withdrawing group) employing a procedure similar to that of Evers, et al. (Evers, et al. I. Prakt. Chem. 333(5), 699-710 (1991)) or Haake et al. (Haake et al. Synthesis - Stuttgart 9, 753-758 (1991)) in a suitable solvent such as ethanol under an inert atmosphere such as argon or nitrogen at reflux. Other procedures (e.g. Wrobel et al. J. Med. Chem.
  • alkyl or substituted alkyl derivatives 24 can be formed by treatment of thiocarbamate 12 or 6 with a suitable base such as sodium hydride in suitable solvent such as DMF under an inert atmosphere, such as argon or nitrogen, followed by addition of an appropriate electrophile such as alkyl or substituted alkyl bromide, iodide, or triflate.
  • Such a transformation of 21 at position-1 can also be effected using a biphasic condition as indicated in Scheme VIII in which alkylation is executed using a biphasic catalyst such as tributylammonium bromide in a suitable solvent such as acetonitrile.
  • a further example of such a modification includes, but is not limited to, heating 21 with triethyl orthoformate to afford 1-substituted derivatives 24.
  • the acylation or carboxylation of the compound 21 at position-1 to give compound 25 can be readily effected by treatment of 12 or 6 with a suitable acylating or carboxylating reagent such as di-t-butyl dicarbonate in the presence of a suitable basic catalyst such as DMAP in a suitable solvent such as acetonitrile under an inert atmosphere such as argon or nitrogen.
  • a suitable acylating or carboxylating reagent such as di-t-butyl dicarbonate in the presence of a suitable basic catalyst such as DMAP in a suitable solvent such as acetonitrile under an inert atmosphere such as argon or nitrogen.
  • the amination of position-1 of compound 21 to give compound 26 can be furnished using a suitable aminating reagent such as chloroamine in the presence of a suitable base such as sodium hydride in a suitable solvent such as THF or diethyl ether following the literature procedure (Metlesics et al. J. Org. Chem.
  • the compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases.
  • These salts include, but are not limited to, the following salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and, as the case may be, such organic acids as acetic acid, oxalic acid, succinic acid, and maleic acid.
  • Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium in the form of esters, carbamates and other conventional “pro-drug” forms, which, when administered in such form, convert to the active moiety in vivo.
  • compositions and treatments which comprise administering to a mammal a pharmaceutically effective amount of one or more compounds as described above as agonists of the progesterone receptor.
  • progesterone receptor agonists of this invention can be utilized in methods of contraception and the treatment and/or prevention of dysfunctional bleeding, uterine leionyomata, endometriosis, polycystic ovary syndrome, and carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, and prostate. Additional uses of the invention include stimulation of food intake.
  • This invention also includes pharmaceutical compositions utilizing the compounds herein, preferably in combination with a pharmaceutically acceptable carrier or excipient.
  • the compounds may be combined with one or more pharmaceutically acceptable carriers or excipients, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium.
  • Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.5 to about 500 mg/kg of animal body weight, preferably given in divided doses two to four times a day, or in a sustained release form For most large mammals, the total daily dosage is from about 1 to 100 mg, preferably from about 2 to 80 mg.
  • Dosage forms suitable for internal use comprise from about 0.5 to 500 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes.
  • Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired.
  • Adjuvents customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
  • compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.
  • active compounds may also be administered parenterally or intraperitoneally.
  • Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringe ability exits. It must be stable under conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacterial and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil.
  • reaction mixture was cooled to ambient temperature and quenched with a saturated aqueous ammonium chloride solution (20 mL). Ethyl acetate (50 mL) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3 ⁇ 15 mL). The combined organic layers were washed with brine and dried with MgSO 4 .
  • reaction mixture was cooled to ambient temperature and quenched with a saturated aqueous ammonium chloride solution (20 mL). Ethyl acetate (100 mL) was added and organic layer was separated. The aqueous layer was extracted with ethyl acetate (3 ⁇ 30 mL). The combined organic layers were washed with brine and dried with MgSO 4 .
  • the white solid was washed with distilled water (3 ⁇ 20 mL) and dissolved in a mixture of ethyl acetate (10 mL) and methanol (10 mL). The solution was applied on a pad of silica gel and eluted with a mixture of ethyl acetate and hexane (1:1).
  • reaction mixture was cooled to ambient temperature and quenched with a saturated aqueous ammonium chloride solution (20 mL). Ethyl acetate (100 mL) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3 ⁇ 30 mL). The combined organic layers were washed with brine and dried with MgSO 4 .
  • the compounds of this invention were tested in the relevant assay as described below and their potency are in the range of 0.01 nM to 5 ⁇ M in the in vitro assays and 0.001 to 300 mg/kg in the in vivo assays.
  • the selected examples are listed in Table 1below.
  • the objective of this assay is the determination of progestational and antiprogestational potency by using a cell proliferation assay in T47D cells. A compound's effect on DNA synthesis in T47D cells is measured.
  • the materials and methods used in this assay are as follows.
  • DMEM:F12(1:1) (GIBCO, BRL) supplemented with 10% (v/v) fetal bovine serum (not heat-inactivated), 100 U/ml penicillin, 100 mg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL).
  • MEM Minimum Essential Medium
  • BRL phenol red-free supplemented with 0.5% charcoal stripped fetal bovine serum, 100 U/ml penicillin, 200 mg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL).
  • BrdU incorporation is measured using a cell proliferation ELISA kit (#RPN 250, Amersham Life Science) according to manufacturer's instructions. Briefly, cells are fixed in an ethanol containing fixative for 30 min. followed by incubation in a blocking buffer for 30 min to reduce background. Peroxidase-labeled anti-BrdU antibody is added to the wells and incubated for 60 min. The cells are rinsed three times with PBS and incubated with 3,3′5,5′-tetramethylbenzidine (TMB) substrate for 10-20 min depending upon the potency of tested compounds. Then 25 ⁇ l of 1 M sulfuric acid is added to each well to stop color reaction and optical density is read in a plate reader at 450 nm within 5 min.
  • TMB 3,3′5,5′-tetramethylbenzidine
  • Square root-transformed data are used for analysis of variance and nonlinear dose response curve fitting for both agonist and antagonist modes. Huber weighting is used to downweight the effects of outliers. EC 50 or IC 50 values are calculated from the retransformed values. JMP software (SAS Institute, Inc.) is used for both one-way analysis of variance and non-linear dose response analyses in both single dose and dose response studies.
  • Trimegestone and medroxyprogesterone acetate (MPA) are reference progestins and RU486 is the reference antiprogestin. All reference compounds are run in full dose-response curves and the EC 50 or IC 50 values are calculated.
  • EC 50 Concentration of a compound that gives half-maximal increase in BrdU incorporation with SE
  • IC 50 Concentration of a compound that gives half-maximal decrease in 0.1 trimegestone induced BrdU incorporation with SE
  • the objective of this procedure is used to evaluate the effect of progestins and antiprogestins on rat uterine decidualization and compare the relative potencies of various test compounds.
  • the materials and methods used in this assay are as follows.
  • Test compounds are dissolved in 100% ethanol and mixed with corn oil (vehicle). Stock solutions of the test compounds in oil (MazolaTM) are then prepared by heating ( ⁇ 80° C.) the mixture to evaporate ethanol. Test compounds are subsequently diluted with 100% corn oil or 10% ethanol in corn oil prior to the treatment of animals. No difference in decidual response was found when these two vehicles were compared.
  • Ovariectomized mature female Sprague-Dawley rats ( ⁇ 60-day old and 230 g) are obtained from Taconic (Taconic Farms, N.Y.) following surgery. Ovariectomy is performed at least 10 days prior to treatment to reduce circulating sex steroids. Animals are housed under 12 hr light/dark cycle and given standard rat chow and water ad libitum.
  • Rats are weighed and randomly assigned to groups of 4 or 5 before treatment.
  • Test compounds in 0.2 ml vehicle are administered by subcutaneous injection in the nape of the neck or by gavage using 0.5 ml. The animals are treated once daily for seven days.
  • animals are given the test compounds and a EC 50 dose of progesterone (5.6 mg/kg) during the first three days of treatment. Following decidual stimulation, animals continue to receive progesterone until necropsy four days later.
  • Doses are prepared based upon mg/kg mean group body weight. In all studies, a control group receiving vehicle is included. Determination of dose-response curves is carried out using doses with half log increases (e.g. 0.1, 0.3, 1.0, 3.0 mg/kg).
  • decidualization is induced in one of the uterine horns by scratching the antimesometrial luminal epithelium with a blunt 21 G needle.
  • the contralateral horn is not scratched and serves as an unstimulated control.
  • rats are sacrificed by CO 2 asphyxiation and body weight measured. Uteri are removed and trimmed of fat.
  • Decidualized (D-horn) and control (C-horn) uterine horns are weighed separately.
  • the increase in weight of the decidualized uterine horn is calculated by D-horn/C-horn and logarithmic transformation is used to maximize normality and homogeneity of variance.
  • the Huber M-estimator is used to down weight the outlying transformed observations for both dose-response curve fitting and one-way analysis of variance.
  • JMP software SAS Institute, Inc. is used for both one-way ANOVA and non-linear dose-response analyses.
  • Route of administration Route the compound is administered to the animals
  • Body weight Mean total animal body weight (default-kg)
  • D-horn Wet weight of decidualized uterine horn (default-mg)
  • Progestational activity Compounds that induce decidualization significantly (p ⁇ 0.05) compared to vehicle control are considered active
  • Antiprogestational activity Compounds that decrease EC 50 progesterone induced decidualization significantly (p ⁇ 0.05)
  • EC 50 for uterine weight Concentration of compound that gives half-maximal increase in decidual response (default-mg/kg)
  • IC 50 for uterine weight Concentration of compound that gives half-maximal decrease in EC 50 progesterone induced decidual response (default-mg/kg)
  • the object of this assay is to determine a compound's progestational or antiprogestational potency based on its effect on PRE-luciferase reporter activity in CV-1 cells co-transfected with human PR and PRE-luciferase plasmids.
  • the materials methods used in the assay are as follows.
  • the growth medium was as follows: DMEM (BioWhittaker) containing 10% (v/v) fetal bovine serum (heat inactivated), 0.1 mM MEM non-essential amino acids, 100 U/ml penicillin, 100 mg/ml streptomnycin, and 2 mM GlutaMax (GIBCO, BRL).
  • the experimental medium was as follows: DMEM (BioWhittaker), phenol red-free, containing 10% (v/v) charcoal-stripped fetal bovine serum (heat-inactivated), 0.1 mM MEM non-essential amino acids, 100 U/ml penicillin, 100 mg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL).
  • Co-transfection is done using 1.2 ⁇ 10 7 cells, 5 mg pLEM plasmid with HPR-B inserted at Sph1 and BamH1 sites, 10 mg pGL3 plasmid with two PREs upstream of the luciferase sequence, and 50 mg sonicated calf thymus DNA as carrier DNA in 250 ml. Electroporation is carried out at 260 V and 1,000 mF in a Biorad Gene Pulser II. After electroporation, cells are resuspended in growth medium and plated in 96-well plate at 40,000 cells/well in 200 ⁇ l.
  • Each treatment consists of at least 4 replicates.
  • Log transformed data are used for analysis of variance and nonlinear dose response curve fitting for both agonist and antagonist modes. Huber weighting is used to downweight the effects of outliers.
  • EC 50 or IC 50 values are calculated from the retransformed values.
  • JMP software SAS Institute, Inc. is used for both one-way analysis of variance and non-linear response analyses.
  • Progesterone and trimegestone are reference progestins and RU486 is the reference antiprogestin. All reference compounds are run in full dose-response curves and the EC 50 or IC 50 values are calculated.
  • Progestational activity Compounds that increase PRE-luciferase activity significantly (p ⁇ 0.05) compared to vehicle control are considered active.
  • Antiprogestational activity Compounds that decrease 3 nM progesterone induced PRE-luciferase activity significantly (p ⁇ 0.05).
  • EC 50 Concentration of a compound that gives half-maximal increase PRE-luciferase activity (default-nM) with SE.
  • IC 50 Concentration of a compound that gives half-maximal decrease in 3 nM progesterone induced PRE-luciferase activity (default-nM) with SE.
  • 4-Amino-3′-fluoro[1,1′-biphenyl]-3-carbonitrile was prepared from 3-fluorophenyl boronic acid and 2-amino-5-bromobenzonitrile according to the procedure of Example 4.
  • a solution of 4-amino-3′-fluoro[1,1′-biphenyl]-3-carbonitrile (6.65 g, 31.3 mmol) in anhydrous THF (100 mL) was treated drop wise at room temperature under nitrogen with methylmagnesium bromide (3.0 M in ether, 21 mL, 63 mmol). The reaction mixture was then heated at gentle reflux for 1.5 hours, cooled to room temperature, and treated with 3N aqueous hydrogen chloride solution (30 mL).
  • reaction mixture was poured into an aqueous saturated sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (3 ⁇ 200 mL). The organic layers were combined, washed with water (200 mL) and brine (100 mL) and dried over magnesium sulfate.
  • the title compound was prepared in a manner similar to Example 16 using 5-(4,4-dimethyl -2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)thiophene-3-carbonitrile and Lawesson's reagent.
  • the product was obtained in the form of yellow crystals: m.p. 258-259° C.
  • 6-Bromo-spiro[4H-3,1-benzoxazine-4,1′-cyclohexane-2-(1H)-one] was prepared from 1-(2-amino-5-bromo-phenyl)cyclohexanol and carbonyl diimidazole according to the procedure of Example 2.
  • reaction mixture was cooled to room temperature and ethyl acetate (100 mL) was added.
  • the organic layers were washed twice with aqueous ammonium chloride (100 mL) and once with brine (100 mL), dried over magnesium sulfate and concentrated.
  • 6-(2-Chloro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one was prepared, according to the procedure of Example 4 from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 2-chlorophenyl boronic acid, as a white solid: mp 181-182 ° C.; MS (ESI) m/z 288 ([M+H] + , 70%), Anal. Calc. For C 16 H 14 ClNO 2 : C, 66.79; H, 4.90; N, 4.87; Found: C, 66.78; H, 4.82; N, 4.55.
  • N-(tert-Butoxycarbonylamino)-3-fluorobenzoic acid (Takagishi et al. Synlett 4, 360-2 (1992), mp 159-161° C.) was deprotected using trifluoroacetic acid to give o-amino benzoic acid, which was then treated with methylmagnesium bromide to afford o-amino dimethyl carbinol.
  • the o-amino dimethyl carbinol (2.23 g, 13.2 mmol) was treated with 1,1-carbonyldiimidizole (2.8 g, 17.2 mmol) in THF (20 mL) at 50° C. for 12 hours.
  • 8-Fluoro-(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronic acid was prepared from 6-bromo-8-Fluoro-4,4-dimethyl-dihydro-benzo[d][1,3]oxazin-2-one using the procedure of Example 4.
  • 6-(3-Bromo-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one was prepared from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronic acid and 1,3-dibromobenzene according to procedure B.

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US09/552,354 1999-05-04 2000-04-19 Cyclothiocarbamate derivatives as progesterone receptor modulators Expired - Lifetime US6436929B1 (en)

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UA2001117768A UA73119C2 (en) 2000-04-19 2000-01-05 Derivatives of cyclic thiocarbamates, pharmaceutical composition including noted derivatives of cyclic thiocarbamates and active ingredients of medicines as modulators of progesterone receptors
US09/552,354 US6436929B1 (en) 1999-05-04 2000-04-19 Cyclothiocarbamate derivatives as progesterone receptor modulators
GEAP20006120A GEP20043181B (en) 1999-05-04 2000-05-01 Cyclothiocarbamate Derivatives as Progesterone Receptor Modulators, Composition Containing Them and Their Use for Treatment Progesterone-Related Maladies
TR2001/03285T TR200103285T2 (tr) 1999-05-04 2000-05-01 Projesteron reseptörü modülatörleri olarak siklokarbamat türevleri.
CZ20013952A CZ20013952A3 (cs) 1999-05-04 2000-05-01 Deriváty cyklothiokarbamátu jako modulátory receptoru pro progesteron
EP00930266A EP1175411B1 (fr) 1999-05-04 2000-05-01 Derives de cyclothiocarbamate tenant lieu de modulateurs du recepteur de progesterone
EA200101181A EA004511B1 (ru) 1999-05-04 2000-05-01 Циклотиокарбаматные производные в качестве модуляторов рецептора прогестерона
NZ515353A NZ515353A (en) 1999-05-04 2000-05-01 Cyclothiocarbamate derivatives as progesterone receptor modulators
HU0203332A HUP0203332A3 (en) 1999-05-04 2000-05-01 Cyclothiocarbamate derivatives, their use as progesterone receptor modulators and pharmaceutical compositions containing them
SG200400081A SG120970A1 (en) 1999-05-04 2000-05-01 Cyclothiocarbamate derivatives as progesterone receptor modulators
PCT/US2000/011749 WO2000066570A1 (fr) 1999-05-04 2000-05-01 Derives de cyclothiocarbamate tenant lieu de modulateurs du recepteur de progesterone
ES00930266T ES2301482T3 (es) 1999-05-04 2000-05-01 Derivados de ciclotiocarbamato como moduladores del receptor de progesterona.
HK02104862.5A HK1043789A1 (zh) 1999-05-04 2000-05-01 作为黄体酮受体调节剂的环硫代胺基甲酸盐衍生物
AU48119/00A AU766801B2 (en) 1999-05-04 2000-05-01 Cyclothiocarbamate derivatives as progesterone receptor modulators
KR1020017014085A KR100732692B1 (ko) 1999-05-04 2000-05-01 프로게스테론 수용체 조절인자인 시클로티오카르바메이트유도체
PL00351083A PL351083A1 (en) 1999-05-04 2000-05-01 Cyclothiocarbamate derivatives as progesterone receptor modulators
CA002371712A CA2371712C (fr) 1999-05-04 2000-05-01 Derives de cyclothiocarbamate tenant lieu de modulateurs du recepteur de progesterone
AT00930266T ATE386729T1 (de) 1999-05-04 2000-05-01 Cyclothiocarbamatderivate als progesteron- rezeptormodulatoren
SK1592-2001A SK15922001A3 (sk) 1999-05-04 2000-05-01 Deriváty cyklotiokarbamátu ako modulátory receptora pre progesterón
BR0010214-8A BR0010214A (pt) 1999-05-04 2000-05-01 Derivados de ciclotiocarbamato como moduladores de receptores de progesterona
JP2000615600A JP4958338B2 (ja) 1999-05-04 2000-05-01 プロゲステロン受容体モジュレーターとしてのシクロチオカルバメート誘導体
DK00930266T DK1175411T3 (da) 1999-05-04 2000-05-01 Cyclothiocarbamatderivater som progesteron-receptormodulatorer
CN008070997A CN1131856C (zh) 1999-05-04 2000-05-01 作为黄体酮受体调节剂的环硫代氨基甲酸酯衍生物
IL14629800A IL146298A0 (en) 1999-05-04 2000-05-01 Cyclothiocarbamate derivatives as progesterone receptor modulators
DE60038108T DE60038108T2 (de) 1999-05-04 2000-05-01 Cyclothiocarbamatderivate als progesteron-rezeptormodulatoren
MXPA01011287A MXPA01011287A (es) 1999-05-04 2000-05-01 Derivados de ciclotiocarbamato como moduladores de receptor de progesterona.
BG106080A BG65277B1 (bg) 1999-05-04 2001-11-02 Циклотиокарбаматни производни като модулатори на прогестеронови рецептори
NO20015381A NO321370B1 (no) 1999-05-04 2001-11-02 Cyklotiokarbamatderivater som progesteronreseptormodulatorer, farmasoytisk preparat omfattende disse, deres anvendelse for fremstilling av medikamenter samt derivater for bruk som medikament.
US10/140,034 US7081457B2 (en) 1999-05-04 2002-05-06 Cyclothiocarbamate derivatives as progesterone receptor modulators
US11/351,002 US7569564B2 (en) 1999-05-04 2006-02-09 Cyclothiocarbamate derivatives as progesterone receptor modulators
US12/420,085 US8329690B2 (en) 1999-05-04 2009-04-08 Cyclothiocarbamate derivatives as progesterone receptor modulators
JP2011249051A JP5523430B2 (ja) 1999-05-04 2011-11-14 プロゲステロン受容体モジュレーターとしてのシクロチオカルバメート誘導体
US13/679,055 US8466146B2 (en) 1999-05-04 2012-11-16 Cyclothiocarbamate derivatives as progesterone receptor modulators
US13/905,515 US8796266B2 (en) 1999-05-04 2013-05-30 Cyclothiocarbamate derivatives as progesterone receptor modulators

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US11/351,002 Expired - Fee Related US7569564B2 (en) 1999-05-04 2006-02-09 Cyclothiocarbamate derivatives as progesterone receptor modulators
US12/420,085 Expired - Fee Related US8329690B2 (en) 1999-05-04 2009-04-08 Cyclothiocarbamate derivatives as progesterone receptor modulators
US13/679,055 Expired - Fee Related US8466146B2 (en) 1999-05-04 2012-11-16 Cyclothiocarbamate derivatives as progesterone receptor modulators
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US12/420,085 Expired - Fee Related US8329690B2 (en) 1999-05-04 2009-04-08 Cyclothiocarbamate derivatives as progesterone receptor modulators
US13/679,055 Expired - Fee Related US8466146B2 (en) 1999-05-04 2012-11-16 Cyclothiocarbamate derivatives as progesterone receptor modulators
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US20090281096A1 (en) 2009-11-12
US20060142280A1 (en) 2006-06-29
US7081457B2 (en) 2006-07-25
US8796266B2 (en) 2014-08-05
US8329690B2 (en) 2012-12-11
US7569564B2 (en) 2009-08-04
US20130261112A1 (en) 2013-10-03
US8466146B2 (en) 2013-06-18
US20130072480A1 (en) 2013-03-21
WO2000066570A1 (fr) 2000-11-09
US20030092711A1 (en) 2003-05-15

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